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Here, we conducted gene expression profiling of sphere-derived castration-resistant prostate cancer stem cells (PCSCs) and identified enhanced sphingolipid de novo biosynthesis with upregulated DEGS2 expression in PCSCs. Silencing of DEGS2 significantly suppressed prostate cancer stem-like traits, cell growth, clonogenicity, and metastasis, while ectopic overexpression of DEGS2 showed the opposite effects. Mechanistically, DEGS2-synthesized phytoceramide activates PI3K-AKT signaling pathway to promote cancer stem-like characteristics, and activation of AKT reversed DEGS2-depletion-inhibited cancer stem-like properties. Clinically, prostate cancer tissues expressed higher levels of DEGS2 compared with adjacent normal tissue, and DEGS2 expression exhibits strong correlations with SOX2, CD133, and Snail expression in primary prostate carcinomas. Collectively, our data illustrate that DEGS2 dictates prostate cancer stem-like properties via the PI3K-AKT pathway, and disruption of this pathway provides potential therapeutic strategies for prostate cancer.<\/jats:p>","DOI":"10.1093\/carcin\/bgaf024","type":"journal-article","created":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T10:36:23Z","timestamp":1747478183000},"source":"Crossref","is-referenced-by-count":1,"title":["Delta 4-desaturase sphingolipid 2 enhances prostate cancer stem-like traits through phytoceramide-mediated PI3K-AKT signaling pathway"],"prefix":"10.1093","volume":"46","author":[{"given":"Yuanyuan","family":"Luo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 ,","place":["China"]},{"name":"Liaoning Province Key Laboratory of Metabolomics , Dalian 116023 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing 100049 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University , Zhongshan Road, Dalian 116011 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 ,","place":["China"]},{"name":"Liaoning Province Key Laboratory of Metabolomics , Dalian 116023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 ,","place":["China"]},{"name":"Liaoning Province Key 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